A systematic review on machine learning approaches in the diagnosis and prognosis of rare genetic diseases.

BACKGROUND: The diagnosis of rare genetic diseases is often challenging due to the complexity of the genetic underpinnings of these conditions and the limited availability of diagnostic tools. Machine learning (ML) algorithms have the potential to improve the accuracy and speed of diagnosis by analyzing large amounts of genomic data and identifying complex multiallelic patterns that may be associated with specific diseases. In this systematic review, we aimed to identify the methodological trends and the ML application areas in rare genetic diseases. METHODS: We performed a systematic review of the literature following the PRISMA guidelines to search studies that used ML approaches to enhance the diagnosis of rare genetic diseases. Studies that used DNA-based sequencing data and a variety of ML algorithms were included, summarized, and analyzed using bibliometric methods, visualization tools, and a feature co-occurrence analysis. FINDINGS: Our search identified 22 studies that met the inclusion criteria. We found that exome sequencing was the most frequently used sequencing technology (59%), and rare neoplastic diseases were the most prevalent disease scenario (59%). In rare neoplasms, the most frequent applications of ML models were the differential diagnosis or stratification of patients (38.5%) and the identification of somatic mutations (30.8%). In other rare diseases, the most frequent goals were the prioritization of rare variants or genes (55.5%) and the identification of biallelic or digenic inheritance (33.3%). The most employed method was the random forest algorithm (54.5%). In addition, the features of the datasets needed for training these algorithms were distinctive depending on the goal pursued, including the mutational load in each gene for the differential diagnosis of patients, or the combination of genotype features and sequence-derived features (such as GC-content) for the identification of somatic mutations. CONCLUSIONS: ML algorithms based on sequencing data are mainly used for the diagnosis of rare neoplastic diseases, with random forest being the most common approach. We identified key features in the datasets used for training these ML models according to the objective pursued. These features can support the development of future ML models in the diagnosis of rare genetic diseases.

Extended phenotype and clinical subgroups in unilateral Meniere disease: A cross-sectional study with cluster analysis.

OBJECTIVES: To define clinical subgroups by cluster analysis in patients with unilateral Meniere disease (MD) and to compare them with the clinical subgroups found in bilateral MD. DESIGN: A cross-sectional study with a two-step cluster analysis. SETTINGS: A tertiary referral multicenter study. PARTICIPANTS: Nine hundred and eighty-eight adult patients with unilateral MD. MAIN OUTCOME MEASURES: best predictors to define clinical subgroups with potential different aetiologies. RESULTS: We established five clusters in unilateral MD. Group 1 is the most frequently found, includes 53% of patients, and it is defined as the sporadic, classic MD without migraine and without autoimmune disorder (AD). Group 2 is found in 8% of patients, and it is defined by hearing loss, which antedates the vertigo episodes by months or years (delayed MD), without migraine or AD in most of cases. Group 3 involves 13% of patients, and it is considered familial MD, while group 4, which includes 15% of patients, is linked to the presence of migraine in all cases. Group 5 is found in 11% of patients and is defined by a comorbid AD. We found significant differences in the distribution of AD in clusters 3, 4 and 5 between patients with uni- and bilateral MD. CONCLUSIONS: Cluster analysis defines clinical subgroups in MD, and it extends the phenotype beyond audiovestibular symptoms. This classification will help to improve the phenotyping in MD and facilitate the selection of patients for randomised clinical trials.

[Diagnostic criteria for Menière's disease according to the Classification Committee of the Bárány Society]. / M. Menière: Diagnostische Kriterien des Internationalen Klassifikationskomitees der Bárány-Gesellschaft.

This paper presents diagnostic criteria for Menière's disease jointly formulated by the Classification Committee of the Bárány Society, The Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society. The classification includes two categories: definite Menière's disease and probable Menière's disease. The diagnosis of definite Menière's disease is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low- to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing, tinnitus and/or fullness) in the affected ear. Duration of vertigo episodes is limited to a period between 20 min and 12 h. Probable Menière's disease is a broader concept defined by episodic vestibular symptoms (vertigo or dizziness) associated with fluctuating aural symptoms occurring in a period from 20 min to 24 h.

Familial clustering and genetic heterogeneity in Meniere's disease.

The aims of this study were to estimate the prevalence of familial cases in patients with Meniere's disease (MD) and to identify clinical differences between sporadic and familial MD. We recruited 1375 patients with definite MD according to the American Academy of Otolaryngology-Head and Neck Surgery criteria, obtaining the familial history of hearing loss or episodic vertigo by direct interview or a postal survey in 1245 cases in a multicenter study. Familial clustering was estimated by the recurrence risk ratio in siblings (λs ) and offspring (λo ) using intermediate and high prevalence values for MD in European population. A total of 431 patients (34%) reported a familial history of hearing loss or recurrent vertigo and 133 patients had a relative with possible MD. After clinical reevaluation, 93 relatives in 76 families were diagnosed of definite MD (8.4%), including three pairs of monozygotic twins. λs and λo were 16-48 and 4-12, respectively. We observed genetic heterogeneity, but most families had an autosomal dominant inheritance with anticipation. No clinical differences were found between sporadic and familial MD, except for an early onset in familial cases. We may conclude that MD has a strong familial aggregation and that sporadic and familial MDs are clinically identical.

Hearing and vestibular disorders in patients with systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) is associated with several comorbidities, including hearing and vestibular disorders. We recently described an increase of SLE prevalence in patients with Menierés disease (MD). The aim of this study is to explore if a subset of SLE patients may have a common inner ear disorder and determine the potential relationship with migraine. METHODS; Eighty-nine patients with SLE (according to the American College of Rheumatology criteria for the diagnosis of SLE) were evaluated for audiovestibular symptoms by a telephone interview carried out by two experienced otoneurologists. Twenty-one patients with SLE were referred to the otoneurology clinic for a detailed clinical history for criteria assessment for MD and a complete audiovestibular examination (audiogram, oculomotor, and caloric testing with video-oculography). RESULTS: Recurrent headache was found in 50/89 patients, and 26 of them had diagnostic criteria for migraine. Twenty-four percent of patients reported sensorineural hearing loss (SNHL) or episodic vertigo. Among the eight patients (9%) with episodic vertigo, one had criteria for definite MD and another two patients had criteria for possible MD. SNHL was found to be associated with a history of episodic vertigo (Fisher's test, p=0.02), but not with headache or migraine. SLE and episodic vertigo were not associated with tinnitus, migraine, lupus nephritis, antinuclear antibodies or antiphospholipid syndrome. CONCLUSIONS: Migraine, SNHL and episodic vertigo are comorbid conditions in patients with SLE, but migraine is not associated with SNHL or vertigo in these patients. However, SNHL and vertigo are associated conditions in SLE, suggesting a common audiovestibular dysfunction.

Rare coding variants involving MYO7A and other genes encoding stereocilia link proteins in familial meniere disease.

The MYO7A gene encodes a motor protein with a key role in the organization of stereocilia in auditory and vestibular hair cells. Rare variants in the MYO7A (myosin VIIA) gene may cause autosomal dominant (AD) or autosomal recessive (AR) sensorineural hearing loss (SNHL) accompanied by vestibular dysfunction or retinitis pigmentosa (Usher syndrome type 1B). Familial Meniere's disease (MD) is a rare inner ear syndrome mainly characterized by low-frequency sensorineural hearing loss and episodic vertigo associated with tinnitus. Familial aggregation has been found in 6-8% of sporadic cases, and most of the reported genes were involved in single families. Thus, this study aimed to search for relevant genes not previously linked to familial MD. Through exome sequencing and segregation analysis in 62 MD families, we have found a total of 1 novel and 8 rare heterozygous variants in the MYO7A gene in 9 non-related families. Carriers of rare variants in MYO7A showed autosomal dominant or autosomal recessive SNHL in familial MD. Additionally, some novel and rare variants in other genes involved in the organization of the stereocilia links such as CDH23, PCDH15 or ADGRV1 co-segregated in the same patients. Our findings reveal a co-segregation of rare variants in the MYO7A gene and other structural myosin VIIA binding proteins involved in the tip and ankle links of the hair cell stereocilia. We suggest that recessive digenic inheritance involving these genes could affect the ultrastructure of the stereocilia links in familial MD.

Summary of recommendations and key points of the consensus of Spanish scientific societies (SEPAR, SEMICYUC, SEMES; SECIP, SENEO, SEDAR, SENP) on the use of non-invasive ventilation and high-flow oxygen therapy with nasal cannulas in adult, pediatric, and neonatal patients with severe acute respiratory failure. / Sumario de las recomendaciones y puntos clave del Consenso de las Sociedades Científicas Españolas (SEPAR, SEMICYUC, SEMES; SECIP, SENeo, SEDAR, SENP) para la utilización de la ventilación no invasiva y terapia de alto flujo con cánulas nasales en el paciente adulto, pediátrico y neonatal con insuficiencia respiratoria aguda grave.

Non-invasive respiratory support (NIRS) in adult, pediatric, and neonatal patients with acute respiratory failure (ARF) comprises two treatment modalities, non-invasive mechanical ventilation (NIMV) and high-flow nasal cannula (HFNC) therapy. However, experts from different specialties disagree on the benefit of these techniques in different clinical settings. The objective of this consensus was to develop a series of good clinical practice recommendations for the application of non-invasive support in patients with ARF, endorsed by all scientific societies involved in the management of adult and pediatric/neonatal patients with ARF. To this end, the different societies involved were contacted, and they in turn appointed a group of 26 professionals with sufficient experience in the use of these techniques. Three face-to-face meetings were held to agree on recommendations (up to a total of 71) based on a literature review and the latest evidence associated with 3 categories: indications, monitoring and follow-up of NIRS. Finally, the experts from each scientific society involved voted telematically on each of the recommendations. To classify the degree of agreement, an analogue classification system was chosen that was easy and intuitive to use and that clearly stated whether the each NIRS intervention should be applied, could be applied, or should not be applied.

Summary of recommendations and key points of the consensus of Spanish scientific societies (SEPAR, SEMICYUC, SEMES; SECIP, SENEO, SEDAR, SENP) on the use of non-invasive ventilation and high-flow oxygen therapy with nasal cannulas in adult, pediatric, and neonatal patients with severe acute respiratory failure.

Non-invasive respiratory support (NIRS) in adult, pediatric, and neonatal patients with acute respiratory failure (ARF) comprises two treatment modalities, non-invasive mechanical ventilation (NIMV) and high-flow nasal cannula (HFNC) therapy. However, experts from different specialties disagree on the benefit of these techniques in different clinical settings. The objective of this consensus was to develop a series of good clinical practice recommendations for the application of non-invasive support in patients with ARF, endorsed by all scientific societies involved in the management of adult and pediatric/neonatal patients with ARF. To this end, the different societies involved were contacted, and they in turn appointed a group of 26 professionals with sufficient experience in the use of these techniques. Three face-to-face meetings were held to agree on recommendations (up to a total of 71) based on a literature review and the latest evidence associated with 3 categories: indications, monitoring and follow-up of NIRS. Finally, the experts from each scientific society involved voted telematically on each of the recommendations. To classify the degree of agreement, an analogue classification system was chosen that was easy and intuitive to use and that clearly stated whether the each NIRS intervention should be applied, could be applied, or should not be applied.

[Reference values for the vestibulo-ocular reflex response to the head shaking and the bithermal caloric tests]. / Valores poblacionales de referencia para video- oculografía en el test de agitación cefálica y la prueba calórica bitérmica.

OBJECTIVE: To obtain reference values for the vestibulo-ocular reflex response to the head-shaking nystagmus and the bithermal caloric test in the spanish population. DESIGN: A descriptive study. SET UP: General hospital. INDIVIDUALS: One hundred and seven healthy sex and age stratified voluntiers were included. The final sample included 97 individuals over 18 years of age. INTERVENTION: Spontaneous nystagmus (SN), head-shaking nystagmus (HSN) and caloric induced nystagmus were explored. The eyes movement was recorded by a video-oculographic system. The SN or HSN was considered significant when at least 6 consecutive beats with a slow phase velocity of 2 degrees/sec were detected. The caloric test was performed with water flow at 250mL/20 s at 30 degrees C and 44 degrees C with an interval of 10 minutes between irrigations. The percentage of canal paresis (CP) and directional preponderance (DP) was calculated using maximum slow phase velocity and the Jongkees index formula. MAIN OUTCOME MEASUREMENTS: Presence of SN, horizontal and vertical SHN, percentage of CP and DP. RESULTS: SN was found in 10,3% individuals (6 women and 4 men). Horizontal HSN was also observed in 9 women and 10 men (19,5%), and vertical HSN in 8 women and 10 men (18,6%). The mean and 95 percentil for CP were 13,10 and 28,60 in women and 11,02 and 27,30 in men. For DP, the mean and 95 percentil were 11,76 and 35,80 in women and 11,58 and 28,65 in men. The 5 percentils for slow phase velocity of nystagmus after each irrigation were 6,30; 5,14; 5,96; 4,02 degrees/s (left ear 44 degrees, right ear 44 degrees, left ear 30 degrees, right ear 30 degrees, respectively) in the group of women; and 5,82; 6,99; 5,67; 4,55 degrees/s in men (with the same irrigation sequence). CONCLUSION: Results presented should be considered as a population-based norms and may be useful as references for water bithermal test for VOG studies. The SN or HSN could be observed in subjects without vestibular pathology.

[Oculomotor response to the vertical cephalic autorotatory test in patients with benign paroxistic positional vertigo of the posterior canal]. / Respuesta oculomotora al test de autorrotación cefálica vertical en pacientes con vértigo posicional paroxístico benigno del conducto posterior.

OBJECTIVE: To evaluate the eye movement response to the head auto-rotation test (HART) in the vertical plane in patients with benign paroxysmal positional vertigo. DESIGN: A transversal, descriptive study. SETTING UP: Outpatient clinic in a general Hospital. INDIVIDUALS: 34 posterior canal BPPV cases with a video-oculographic diagnosis, older than 18 years old, 7 of them were not able to perform the HART. INTERVENTION: HART was performed by a an electrooculographic system with simultaneous recording of head movement by an acelerometer in the vertical plane (Vorteq, Micromedical Instruments). The HART with eyes fixation was performed 3 times to determine its reliability. MAIN OUTCOME MEASURES: Gain, asymmetry and phase for the vertical VOR respectively. A statistical analysis was carried out to determine the test reliability and the number of individuals with an abnormal result. RESULTS: Gain is the only variable that showed a reproducible result in the HART for the active head movement at 1-2 Hz (test-retest reliability 0.83-0.89). The values of gain showed a moderate correlation at the frequencies 1-3 Hz (correlation 0.60-0.87). Asymmetry and phase were not reproducible variables (correlation < 0.55). Thirteen of 27 (48%) patients presented a decrease of the vertical gain, another 13 showed normal values and one case showed raised values. CONCLUSION: Gain is the only useful variable in the vertical HART. Forty-eight percent of patients with posterior canal BPPV have a reduced vertical gain, suggesting an impairment of inferior vestibular nerve function.

Menière's disease.

Menière's disease (MD) is a chronic multifactorial disorder of the inner ear characterized by episodic vestibular symptoms associated with sensorineural hearing loss, tinnitus, and aural pressure. Epidemiologic and genomic evidence supports a genetic susceptibility with multiple biochemical pathways involved, including the endocrine system, innate immune response, and autonomic nervous system. Allergens, infectious agents, vascular events, or genetic factors could modify inner-ear homeostasis and trigger MD. The diagnosis of MD is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low- to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing loss, tinnitus, and/or fullness) in the affected ear. Headache is also found during the attacks and bilateral involvement is found in 25-40% of cases. Audiologic and vestibular assessment is recommended to monitor the clinical course. The treatment of MD is symptomatic to obtain relief of vestibular episodes and preventive to limit hearing loss progression. Treatment options include sodium restriction, betahistine, intratympanic gentamicin, or steroids and eventually surgery, such as cochlear implantation.

Quantitative histochemistry of phosphorus in the vestibular gelatinous membrane: an electron probe X-ray microanalytical study.

Electron probe X-ray microanalysis was used to study the phosphorus concentration in the otolithic gelatinous membrane of the saccule and the utricle with scanning electron microscopy. The otolithic membranes were plunge-frozen in liquid N2 and freeze-dried. Quantitative analysis was carried out with an energy dispersive detector using the peak-to-background ratio method and different concentrations of KH2PO4 salts dissolved in dextran solutions. The otolithic gelatinous membrane consists of a 25-30 microns-thick layer overlying the cilia of the hair cells. Elements detected in the gelatinous membrane are: Na, P, S, Cl, K and Ca. Although Student's t-test did not show significant differences between saccular and utricular concentrations of phosphorus, the distribution of this element in the two organs was different. Regression analysis established that the concentrations of phosphorus in the saccular and utricular gelatinous membrane were dependent. The regression equation was: y = 18.02x2 + 133.9 (r = 0.83, P < 0.05) where y is the concentration of phosphorus in the utricle, and x2 the concentration of phosphorus in the saccule. The findings obtained in the present study could be related to structural differences in organic phosphate residues of the phosphoproteins associated to collagen, or to different polyphosphoinositide turnover rates in the cell membrane.

Cell surface patterns in normal human oral gingival epithelium. A quantitative scanning electron microscopy approach.

We used scanning electron microscopy to study the morphological surface patterns of cells that cover the attached gingiva and intervestibular papilla of the human oral gingival epithelium. Five patterns are described on the basis of the overall appearance of morphological surface markers: microvilli, parallel, fingerprint, reticular and pitted. Statistical analyses detected significant differences in the frequency of each pattern in both regions of the oral gingival epithelium, and showed the reticular and fingerprint types to predominate. We propose that our description of the different morphological surface types may be of use as a standard for subsequent cytological studies and characterizations of morphological alterations in diseased gingiva.

Surface expression and distribution of Fc receptor III (CD16 molecule) on human natural killer cells and polymorphonuclear neutrophils.

Human natural killer cells and polymorphonuclear neutrophils constitutively express the low-affinity IgG Fc receptor (Fc gamma RIII, CD16 molecule). To investigate cell surface morphology, antigenic receptor density, and topographical distribution of Fc gamma RIII on the plasma membrane of natural killer cells and polymorphonuclear neutrophils, conventional scanning electron microscopy (SEM), flow cytometry, and immunoscanning electron microscopy were used. Fc gamma RIII was detected with an indirect immunogold labeling procedure, and receptors were visualized in the backscattered and secondary electron imaging mode of SEM. Natural killer cells showed a cell surface morphology compatible with lymphocytic differentiation characterized by microvilli and microridges. Polymorphonuclear neutrophils showed surface features characterized by ridges with folds and scattered short microvilli. Natural killer cells displayed a lower cell labeling density, whereas polymorphonuclear neutrophils showed a high level of expression of Fc gamma RIII on the plasma membrane by quantitative analysis with SEM in the backscattered electron imaging mode. Flow cytometry analysis confirmed these findings. Analysis of the topographical distribution of Fc gamma RIII antigenic receptor sites by SEM in the backscattered and secondary electron imaging modes showed that Fc gamma RIII on natural killer cells are randomly distributed, whereas Fc gamma RIII are located on ridges and folds of the plasma membrane of polymorphonuclear neutrophils. These observations suggest that natural killer cells and polymorphonuclear neutrophils differ in their levels of expression and topographic distribution of Fc gamma RIII on the plasma membrane. This different spatial distribution of Fc gamma RIII would provide morphological evidence of certain cellular functions mediated by natural killer cells and polymorphonuclear neutrophils.

Electron probe microanalysis of gentamicin-induced changes on ionic composition of the vestibular gelatinous membrane.

Gentamicin-induced changes in ionic composition in the otolithic membrane of adult OF1 mice were evaluated in the gelatinous layers of the saccule and utricle by quantitative electron probe X-ray microanalysis. The otolithic membranes were plunge-frozen and freeze-dried to prevent the redistribution of elements. Quantitative analysis was carried out with an energy dispersive detector using the peak-to-background (P/B) ratio method and different salts dissolved in dextran as standards to calibrate the P/B ratio against the concentration of the elements P, S and K in the microprobe. Gentamicin selectively decreased the concentrations of P (P < 0.001) and S (P < 0.01) in the gelatinous membrane of the saccule, and had no effect in the utricle. The concentration of K also increased in the utricular gelatinous membrane (P < 0.05). The mechanism of ototoxicity in the gelatinous membrane is unknown, but the ability of aminoglycosides to block calcium channels may induce disturbances in the ionic equilibrium of the endolymphatic fluid, and thus affect the biochemical composition of the gelatinous membrane. This technique can be useful to evaluate the distribution of ions in the process of drug-induced ototoxicity.

Mechanically induced calcium increases in isolated vestibular hair cells of the guinea pig.

Intracellular Ca2+([Ca2+]i) is elevated by depolarization or mechanical stimulation in some hair cell systems. It is not clear whether both these stimuli promote Ca2+ entry in mammalian vestibular hair cells. We monitored [Ca2+]i with the indicator fluo-3 in isolated type I vestibular hair cells of the guinea pig maintained in Hanks' balanced salt solution (HBSS). Mechanical stimulation by bolus application of HBSS led to an immediate rise of [Ca2+]i. The effect depended upon the presence of extracellular Ca2+([Ca2+]o) and no increase occurred in calcium-free HBSS supplemented with calcium-chelators. When the cells were depolarized by bolus application of KCl (final concentration, 100 mM KCl in modified HBSS), the increase in [Ca2+]i was similar to that elicited by HBSS. In the absence of [Ca2+]o, the application of KCI/HBSS led to a slow sustained increase in the fluorescence of the cells suggesting release of calcium from intracellular stores. Finally, treatment of cells with BAPTA prior to mechanical stimulation prevented the rise in [Ca2+]i indicating the need for intact stereociliary tip-links. The results are consistent with the hypothesis that mechanical stimulation elevates [Ca2+]i in isolated vestibular hair cells via calcium influx through mechanotransduction channels.

X-ray microanalytical determination of P, S and K concentrations in the gelatinous membrane of the utricle.

Electron probe X-ray microanalysis was used to determine the concentrations of P, S and K (Cp, CS, CK) in the gelatinous membrane of the mouse utricle. The otolithic membranes were plunge-frozen in liquid N2, freeze-dried and carbon-coated. Quantitative analysis was carried out with an energy dispersive detector using the peak-to-background ratio method and different concentrations of KH2PO4 and K2SO4 salts dissolved in dextran solutions to calibrate the microprobe. P, S and K were measured and their concentrations plotted as bar graphs to study the frequency distributions. Regression analysis revealed a dependence between the concentrations of P and K (CK = 1454.10 - 2.83 CP, r = -0.68745, p < 0.05), and P and S (CS = 43.18 + 0.23 CP, r = 0.66949, p < 0.05); however, no correlation was found between CK and CP (r = -0.25424). The findings obtained in the present study show an inverse relationship between P and K ions, and direct relationship between P and S in the gelatinous membrane of the utricle.

Gentamicin ototoxicity in otoconia: quantitative electron probe X-ray microanalysis.

Chronic gentamicin ototoxicity was evaluated in the otolithic membrane of adult OF1 mice at the otoconial layer of the saccule and utricle by quantitative electron probe X-ray microanalysis of Ca and K. The otolithic membranes were plunge-frozen and freeze-dried. The analysis was carried out with an energy dispersive detector using the peak-to-back-ground ratio method and different inorganic salts of Ca and K as standards to calibrate the microprobe. Ca and K in the otoconia are related via a linear function in both the saccule and the utricle. This association is not maintained after exposure to gentamicin, which suggests that this aminoglycoside antibiotic interferes with the Ca-K equilibrium in the otoconia. A dose of 200 mg/kg gentamicin twice a day for 5 days did not affect Ca in the mineral phase of the otoconia, but did increase K in both saccular (p < 0.05) and utricular (p < 0.01) otoconia. These increases in K may reflect a modification in the composition of the endolymph, resulting from cellular damage at the plasma membrane.